Valsartan belongs to group of angiotensin II antagonists which are useful in the treatment of hypertension, anxiety, glaucoma and cardiac attacks. Valsartan is an orally active specific angiotensin II antagonist acting on the AT1 receptor subtype. It is useful in regulating high blood pressure and cardiac insufficiency.
The process for preparing Valsartan is disclosed in U.S. Pat. No. 5,399,578 as shown by schematic diagram in Scheme-I:

The synthesis involves the conversion of 4-bromomethyl-2′-cyanobiphenyl of formula (A) to carbaldehyde of formula (C). Further, it is condensed with methyl ester of L-valine of formula (D) under reducing condition to give N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (E), which is purified by flash chromatography. Reaction of compound of formula (E) with n-Valeroyl chloride of formula (F) in presence of triethylamine gives N-valeryl-N-[(2′-cyanobiphenyl-4-yl)methyl]-(L)-valine methyl ester of formula (G). After purification by flash chromatography, compound of formula (G) is cyclized in presence of tributyltin azide in xylene and converted to Valsartan (I) in presence of sodium hydroxide.
The condensation of L-valine methyl ester and carbaldehyde requires reagent like sodium cyanoborohydride, which are costly. Also process involves purification of intermediates by flash chromatography, which is lengthy and cumbersome and difficult to adopt at commercial scale.
According to another embodiment given in U.S. Pat. No. 5,399,578 the carbaldehyde compound (C) is condensed with Tosylate salt of L-valine benzyl ester in presence of sodium cyanoborohydride to give benzyl ester analogue of compound of formula (E). This compound is purified by converting it into its hydrochloride salt and then breaking the hydrochloride salt with sodium bicarbonate. The purified compound is then reacted with n-Valeroyl chloride and cyclized with tributyltin azide in xylene. Further hydrogenation using Palladised carbon catalyst gives Valsartan (I).
The another approach for the synthesis of Valsartan is disclosed in general description of Bioorganic and Medicinal Chemistry Letters, Vol. 4 (1), 1994 as shown below in Scheme-II:
wherein R is —CH(CH3)2 in above scheme represents Valsartan(I).
So, the condensation of compound Halomethylbiphenyl derivative with L-valine ester is one of the important steps for the synthesis of Valsartan. It was observed by us that the condensation of compound of formula (II) with L-valine ester of formula (III) generates about 6-10% w/w unwanted dimeric impurity of formula (IVb) along with desired compound of formula (IVa) as shown in Scheme-III. This results in the poor yield and quality of the product and requires additional purification step.

Therefore, there is a need to have simple, easy to handle and cost effective process for the preparation of Valsartan and its intermediates. Also, it is required to prepare its intermediate (IVa), substantially free from its dimeric impurity of formula (IVb).
The inventors of the present invention has surprisingly found that the dimeric impurity of formula (IVb) can be easily removed from desired compound of formula (IVa) by converting it into organic salt of formula (IV), which can be condensed directly with n-valeroyl chloride without further purification. Thus cumbersome technique of separation like column chromatography can be avoided. The compound of formula (IV) is stable and non-hygroscopic in nature. The use of compound (IV) in synthesis of Valsartan results in improved quality of product containing less percentage of impurities.
It was also surprisingly observed by us that condensation of compound of formula (IV) with n-valeroyl chloride of formula (F) takes place easily and rapidly in the presence of base and water, optionally in presence of organic solvent to give compound of formula (VI). The crude compound of formula (VI) can be used further without purification to give Valsartan (I).